23834 research outputs found
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Informatics at the frontier of cancer research
Full text linkDigitized healthcare data, high-throughput profiling technologies, and data repositories have facilitated the emergence of a new era of cancer research. Each data stream requires specialized analysis methods for interpretation. The data-driven era of cancer research requires the development, enhancement, and sustainment of informatics technology software infrastructure, including fundamental methodology development in artificial intelligence and data science. We review current and emerging informatics technology developments for cancer research and discovery, spanning molecular and cellular characterizations, image analysis, informatics, and therapeutics. Summarizing the diverse methods and applications of informatics throughout cancer research identifies themes and emerging areas for the next generation of cancer research. This article is part of a special series: Driving Cancer Discoveries with Computational Research, Data Science, and Machine Learning/AI
Mendelian randomization study of sleep traits and risk of colorectal cancer
Full text linkA potential association of endogenous circadian rhythm disruption with risk of cancer development has been suggested, however, epidemiological evidence for the association of sleep traits with colorectal cancer (CRC) is limited and often contradictory. Here we investigated whether genetically predicted chronotype, insomnia and sleep duration are associated with CRC risk in males, females and overall and according to CRC anatomical subsites using Mendelian randomization (MR). The two-sample inverse variance weighted (IVW) method was applied using summary-level data in up to 58,221 CRC cases and 67,694 controls and genome-wide association data of genetic variants for self-reported sleep traits. Secondary analyses using alternative instruments and sensitivity analyses assessing potential violations of MR assumptions were conducted. Genetically predicted morning preference was associated with 13% lower risk of CRC in men (O
Thrombotic microangiopathy after kidney transplantation: Insights into genetic etiology and clinical outcomes
Full text linkINTRODUCTION: Thrombotic microangiopathy (TMA), characterized by small-vessel thrombosis caused by endothelial injury, presents significant diagnostic and treatment challenges in kidney transplantation.
METHODS: To investigate the factors associated with posttransplant TMA, we conducted a retrospective study of 3535 kidney transplant recipients at our center from 2008 to 2023.
RESULTS: Sixty-eight patients were diagnosed with TMA, and 93% (63 of 68) underwent genetic testing. Patients were categorized into 3 groups based on the TMA etiology. Group 1 (
CONCLUSION: Our findings underscore the need for comprehensive pre and posttransplantation genetic testing to predict and manage the risk of TMA and prevent graft loss. CNIs may exacerbate the risk of posttransplant TMA in the presence of other complement-activating factors. Our study also highlights the importance of personalized strategies and early interventions based on the functional assessment of variants of uncertain significance (VUS)
Clinical trials for Wolfram syndrome neurodegeneration: Novel design, endpoints, and analysis models
Full text linkOBJECTIVE: Wolfram syndrome, an ultra-rare condition, currently lacks effective treatment options. The rarity of this disease presents significant challenges in conducting clinical trials, particularly in achieving sufficient statistical power (e.g., 80%). The objective of this study is to propose a novel clinical trial design based on real-world data to reduce the sample size required for conducting clinical trials for Wolfram syndrome.
METHODS: We propose a novel clinical trial design with three key features aimed at reducing sample size and improve efficiency: (i) Pooling historical/external controls from a longitudinal observational study conducted by the Washington University Wolfram Research Clinic. (ii) Utilizing run-in data to estimate model parameters. (iii) Simultaneously tracking treatment effects in two endpoints using a multivariate proportional linear mixed effects model.
RESULTS: Comprehensive simulations were conducted based on real-world data obtained through the Wolfram syndrome longitudinal observational study. Our simulations demonstrate that this proposed design can substantially reduce sample size requirements. Specifically, with a bivariate endpoint and the inclusion of run-in data, a sample size of approximately 30 per group can achieve over 80% power, assuming the placebo progression rate remains consistent during both the run-in and randomized periods. In cases where the placebo progression rate varies, the sample size increases to approximately 50 per group.
CONCLUSIONS: For rare diseases like Wolfram syndrome, leveraging existing resources such as historical/external controls and run-in data, along with evaluating comprehensive treatment effects using bivariate/multivariate endpoints, can significantly expedite the development of new drugs
Management aspects of medical therapy in Graves disease
Full text linkOBJECTIVE: Graves disease (GD) is the most common cause of hyperthyroidism. Treatment options include antithyroid drugs (ATDs), radioactive iodine, and surgery. In this review, we focus on the medical aspects of managing GD.
METHODS: The authors conducted a literature review of PubMed to include studies and review articles on GD management, ATDs, long-term safety of antithyroid drugs, hyperthyroidism in pregnancy, Graves ophthalmopathy, and special circumstances related to hyperthyroidism.
RESULTS: In adjunction to ATDs, medical management for GD also includes beta-blockers, glucocorticoids, and iodine containing agents. ATDs are currently the preferred option for initial management of GD, reflecting a shift in practice observed in the United States over the past 2 decades. ATDs in appropriate doses are well-tolerated and safe when used for longer duration, during pregnancy, and other circumstances discussed in this article. Routine thyroid function tests are important for monitoring. Thyrotropin receptor antibody plays an essential role in determining duration of treatment and assessing the likelihood of recurrence.
CONCLUSION: Medical management of GD with antithyroid drug is safe and effective. Long-term use beyond 24 months in patients with elevated thyrotropin receptor antibody is a reasonable alternative option to surgery and radioactive iodine due to higher rates of remission
The cognitive profile of older adults with treatment-resistant depression: An analysis of the OPTIMUM randomized controlled trial
Full text linkOBJECTIVE: Major depressive disorder in older adults (late-life depression; LLD) is frequently associated with cognitive impairment, and some deficits (e.g., executive function) have been associated with a higher level of treatment resistance. However, the cognitive profile of treatment-resistant LLD (TR-LLD) has not been characterized. We hypothesized that patients with TR-LLD would show deficits in cognitive function, especially executive function, and that executive function deficits would predict poorer response to pharmacotherapy.
DESIGN: Secondary analysis of baseline cognitive data from OPTIMUM, a multicenter RCT evaluating pharmacotherapy strategies for TR-LLD.
SETTING: Five outpatient academic medical centers (4 US, 1 Canada).
PARTICIPANTS: About 369 participants aged 60 and older from the OPTIMUM study.
MEASUREMENTS: Baseline scores on individual tasks and composite scores from the NIH Toolbox-Cognition Battery were transformed into demographically-adjusted T-scores and compared to published norms. Impairments in the set shifting and inhibitory control tasks were investigated as predictors of depressive symptom change following treatment using ANCOVA models.
RESULTS: Participants had low performance on tasks evaluating inhibitory control, processing speed, verbal/nonverbal memory, and the fluid composite, but normative performance on working memory and set shifting. Participants had high estimated premorbid IQ (superior Performance on oral reading recognition). Age and physical comorbidity negatively associated with processing speed. Impairments in set shifting predicted less improvement in depressive symptoms; impairments in inhibitory control did not.
CONCLUSIONS: Participants with TR-LLD presented with broad cognitive deficits relative to healthy norms. Given poorer outcomes following standard pharmacotherapy associated with impaired set shifting, future research needs to identify alternative treatment strategies
Molecular basis for human respiratory syncytial virus transcriptional regulator NS1 interactions with MED25
Full text linkThe Mediator complex facilitates interactions between transcription factors and RNA polymerase II, a process that is required for host gene transcription, including in response to viral infections. Among the many subunits in the Mediator complex, the MED25 subunit has been shown to be a target for viral activators during infection. Here we provide the molecular basis for the interaction between human respiratory syncytial virus (hRSV) nonstructural 1 protein (NS1) and the activator interaction domain (ACID) of MED25. The X-ray crystal structure of the complex revealed that NS1 straddles and binds two faces of MED25 ACID. This interaction is distinct from previously known viral activators. Importantly, our data support the conformational flexibility of viral transcriptional regulators. Furthermore, ChIP-seq and RNA-seq analysis identified the ATF3 transcription factor and a role for NS1/Mediator/ATF3 interaction in host gene regulation in hRSV infections. Our findings provide a molecular basis for hRSV NS1-based regulation of host gene transcription and reveal how viruses exploit the conformational heterogeneity at fuzzy transcription activator interfaces
Reprogramming aerobic metabolism mitigates Streptococcus pyogenes tissue damage in a mouse necrotizing skin infection model
Full text linkDisease tolerance is a host response to infection that limits collateral damage to host tissues while having a neutral effect on pathogen fitness. Previously, we found that the pathogenic lactic acid bacterium Streptococcus pyogenes manipulates disease tolerance using its aerobic mixed-acid fermentation pathway via the enzyme pyruvate dehydrogenase, but the microbe-derived molecules that mediate communication with the host\u27s disease tolerance pathways remain elusive. Here we show in a murine model that aerobic mixed-acid fermentation inhibits the accumulation of inflammatory cells including neutrophils and macrophages, reduces the immunosuppressive cytokine interleukin-10, and delays bacterial clearance and wound healing. In infected macrophages, the aerobic mixed-acid fermentation end-products acetate and formate from streptococcal upregulate host acetyl-CoA metabolism and reduce interleukin-10 expression. Inhibiting aerobic mixed-acid fermentation using a bacterial-specific pyruvate dehydrogenase inhibitor reduces tissue damage during murine infection, correlating with increased interleukin-10 expression. Our results thus suggest that reprogramming carbon flow provides a therapeutic strategy to mitigate tissue damage during infection
Role of glucuronoxylomannan and steryl glucosides in protecting against cryptococcosis
Full text linkThe development of vaccines for fungal diseases, including cryptococcosis, is an emergent line of research and development. In previous studies, we showed that
